5-carbamyloxy-3alpha, 4, 5, 6, 7, 7alpha-hexahydro-4, 7-methanoindan



United States Patent 3,347,907 5-CARBAMYLOXY-3a,4,5,6,7,7a-HEXAHYDRO- 4,7-METHANOINDAN Burton Kendall Wasson, Valois, Quebec, and John M.

Parker, Montreal, Quebec, Canada, assignors to Charles E. Frosst & Co., Montreal, Quebec, Canada, a corporation of Canada No Drawing. Filed May 19, 1964, Ser. No. 368,701 1 Claim. (Cl. 260-482) The present invention relates to 5-carbamyloxy-3a,4,5, 6,7,7a-hexahydro-4,7-methanoindan and methods for its preparation.

In accordance with the present invention it has now been found that 5-carbamyloxy-3a,4,5,6,7,7a-hexahydro- 4,7-methanoindan is particularly useful as a muscle relaxing compound.

The compound of the present invention is prepared by reacting 5-hydroxy-3a,4,5,6,7,7a-hexahydro-4,7-rnethanoindan with phosgene to form the corresponding chlorocarbonate and treating said chlorocarbonate with ammonium hydroxide to form the corresponding carbamate.

The compound of the present invention has been determined to have unusual muscle relaxing properties by submitting it to pharmacological tests. The results and the test procedure used are as follows:

Acute toxicity.The acute toxicity of the invented compound was determined in mice as discussed in the presentation of T. Sollman, page 37 of the Manual of Pharmacology, 8th edition, Saunders Press, 1957, Philadelphia. The lethal and efiective dose of the compound in mice and rats was determined as follows: Intraperitoneal injections of the compound in a gum acacia suspension were given to groups of animals. Using five animals to a group, the animals were observed for five days and the number of deaths recorded. The percent mortality was plotted against logarithm of the dose and the LD and ED value determined by the method of Litchfield and Wilcoxon (J. Pharmacol. and Exp. Therap., vol. 96, 99- 113, 1949).

No. of mice used LD ip., mice: 648 mg./kg., limits (558.6751.7) '80 PD ip., mice: 225 mg./kg., limits (200253) 80 LD orally, mice: 4050 mg./kg., limits (26934091) 6O PD orally, mice: 2930 -mg./kg., limits (19044509) 60 LD orally, rats: 3170 mg./kg., limits (2092-4803) 40 PD orally, rats: 2100 mg./kg., limits Efiect on hind-limb rigidity in the dog (Spinal anoxia.Using the technique of S. Gelfan and I. M. Tarlov as discussed in the Journal of Physiol. (1959), 146, 594- 617, animals were tested to determine the effect of our compound on the hind-limb rigidity of the dog.

Before Drug: Tension of 14 lbs. had no effect on rigidity.

After Drug: 3.5 lbs. tension caused legs to bend easily (150 mg./kg. ip.); 9.0 lbs. tension caused legs to bend (200 mg./kg. orally).

Effect on muscle potential in the rigid hind-limb 0f the d0g.Using animals prepared by the techniques of S. Gelfan and I. M. Tarlov, our compound was tested to determine its effect on the muscle potential in the rigid hind-limb of the dog. At 150 mg./kg. ip. there was a marked decrease in the muscle potential minutes after injection. This condition lasted for approximately 35 minutes. Relaxation of muscles in both hind legs was noticeable for 1 /2 hours.

3,347,97 Patented Oct. 17, 1967 Antico-nvulsant activity in mice.Audiogenic Seizure Method: ED -estimated mg./kg. ip. Electroshock Method: ED --100 mg./kg. ip.

This was determined by measuring the ability of 5 carbamyloxy 3a,4,5,6,7,7a hexahydro 4,7 methanoindan to protect mice against the maximal convulsant action of electroshock and audiogenic stimulation. The maximal electroshock test has been used because of its simplicity and reliability and is one of several commonly employed procedures for the assay of anticonvulsant drugs (Toman et al., J. Neurophysiol., 9:331:1946; Swinyard, J. Am. Pharm. A. (Scient. Ed.), 38:201:l949; Chen and Ensor, Arch. Neurol. & Psychiat., 63:56:1950; Swinyard et al., J. Pharm. Exptl. Therap., 106:31921952 and others).

Pr0cedure.Using the technique of Woodbury and Davenport, Arch. Int. Pharmacodyn, 92:97:1952 (Swinyard et al., J. Pharm. Exptl. Therap., 106:319: 1952) maximal electroshock seizures were induced in male and female albino mice, 1820 gms., by means of a electronic stimulator with current intensity of 104 v. (60 cycle AC, .2 sec. duration, corneal electrodes). Ten mice were used at each dose level. 5-carbamyloxy-3a,4,5, 6,7,7a-hexahydro-4,7-methanoindan was injected intraperitoneally as a suspension in 60% gum acacia solution. The control animals received only gum acacia. The mice were tested 20 minutes after injection.

The ED dose of S-carbamyloxy-3a,4,5,6,7,7a-hexahydro-4,7-methanoindan required to protect 50% of the animals was determined graphically by the method of Litchfield and Wilcoxon, J. Pharm. Exptl. Therap., 9629921949.

A seizure chamber of similar dimensions to that used by N. P. Plotnikolf and D. M. Green (J. Pharm. Exptl. Therap., 119:294-295z1957) for the evaluation of drugs with protective action against audiogenic seizures was used.

Audiogenic seizures in various strains of mice have been reported by Frings, Frings and Kivert (J. Mamm., 32:60:1951), and Frings and Frings (J. Acoust. Soc. Amer., 24:163z1952). The mice used in our experiments were the offspring of a cross between male DBA/ 2 Cum. strain of mice susceptible to audiogenic seizure and female Connaught strain. The test procedure is identical to that used by G. B. Fink and E. A. Swinyard (J Pharm. Exptl. Therap., 127:318 1959).

Strychnine toxicity in mica-At doses of 200, 150, mg./kg. subcutaneous protected all animals from strychnine deaths. At doses of 50 mg./kg. subcutaneous the drug had no significant effect.

The experiments were carried out by a technique similar to that used by F. M. Berger (Ann. of NY. Acad. Sc., 123:690:1956), J. F. Sherman (Science, 123:1170- 1171:1956).

The 5-carbamyloxy-3a,4,5,6,7,7a-hexahydro-4,7-methanoindan was injected subcutaneously in mice; strychnine was administered by the intraperitoneal route 25 minutes later in a dose of 1.5 rug/kg. Controls (receiving strychnine only) were run concurrently with each experiment; 10 animals were used for each dose level.

Pentobarbital potentiation in mica-200 mg./ kg. ip. increased sleeping time by 321.7%. 100 mg./kg. ip. increased sleeping time by 111.3%.

The experiments were conducted with male albino mice, 18-20 gm. in weight.

Pentobarbital sodium, 50 mg./kg. was injected intraperitoneally 15 minutes after the administration of S-carbamyloxy-3a,4,5,6,7,7a hexahydro 4,7 methanoindan l Sleeping time was taken as the time elapsed from the loss of righting reflex to its return. (I. B. Kahn, Jr., J. Pharm., Exptl. Therap., 109:292z1953; A. Goldin, D.

Dennis, J. M. Venditti, S. R. Humphreys, Sc., 1211364- 365z1955).

EXAMPLE I -carbam yl0xy-3 a,4 ,5 ,6, 7,7a-hexalzyd 1'0-4 ,7-me thanoindan A solution of 25 grams of 5-hydroxy-3a,4,5,6,7,7a-hexahydro-4,7-methanoindan in 70 cc. of tetrahydrofuran was added dropwise during one hour to a solution of 24 grams of phosgene in 70 cc. of tetrahydrofuran maintained at 0-5 C. The solution was stirred for thirty minutes in an ice-bath and then for one hour at room temperature. The solution containing the chlorocarbonate was added dropwise during one hour to 120 cc. of concentrated ammonium hydroxide maintained at -20 C. The mixture was diluted with water and extracted with ethyl ether. The ethereal solution was evaporated to dryness. Crystallization of the residue from benzene-petroleum ether gave 27.9 grams of 5-carbamyloxy-3a,4,5,6,7,7a-hexahydro-4,7-rneth-anoindan. Further recrystallization from the same solvents aiforded an analytical sample melting at 124-125 C.

Analysis.Calculated for C H NO C, 67.65; H, 8.79; N, 7.17. Found: C, 67.56; H, 8.92; N, 7.11.

EXAMPLE II 5-carbamyl0xy-3a,4,5,6,7,7a-hexahydr0-4,7-methanoindan S-hydroxy-3a,4,5,6,7,7a hexahydro-4,7rnethanoindan (12.5 grams) was dissolved in cc. of benzene. Potassium cyanate (13.3 grams) was added to the solution followed by 18.8 grams of trifiuoroacetic acid. During the addition of the trifiuoroacetic acid the internal temperature rose from 25 to 38 C. The mixture was stirred for four hours. The mixture was diluted with about cc. of water and then extracted with ethyl ether. The ethereal layer was evaporated to a smaller volume with crystallization occurring. The solids were collected and recrystallized from ethyl ether-petroleum ether (30-60") to give 5.8 grams of S-carbamyloxy-3a,4,5,6,7,7a-hexahydro-4,7- methanoindan having a melting point of -127 C. The mixed melting point of this product with that from EX- ample I showed no depression. The infrared spectral curve was essentially the same as that of the product from Example I.

We claim:

S-carbamyloxy 3a,4,5,6,7,7a hexahydro 4,7 methanoindan.

References Cited UNITED STATES PATENTS 2,846,465 8/1958. Boehrne et al 260-482 2,847,454 8/1958 Boehrne et a1 260482 FOREIGN PATENTS 1,041,495 10/1958 Germany.

RICHARD K. JACKSON, Primary Examiner.

LORRAINE A. WEINBERGER, Examiner.

A. P. HALLUIN, Assistant Examiner. 

